On August 14, 2023, the FDA approved melphalan hydrochloride for injection/Hepatic Delivery System (HDS; Hepzato Kit; Delcath Systems) as a liver-directed treatment for use in adults with uveal (or ocular) melanoma and unresectable hepatic metastases that affect <50% of the liver and who have no extrahepatic disease, or extrahepatic disease that is limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation. The FDA granted this approval an orphan drug designation.
Melphalan hydrochloride is a bifunctional alkylating chemotherapy (originally approved in 1964) that is active against selected human neoplastic diseases. This novel agent contains melphalan hydrochloride, which is administered via the HDS device into the hepatic artery.
The FDA approved this new agent based on the efficacy results of the FOCUS study, a phase 3, single-arm, multicenter, open-label clinical trial (NCT02678572) that included 91 patients with uveal melanoma and unresectable hepatic metastases. The enrolled patients were allowed to have limited extrahepatic disease in the bone, subcutaneous sites, lymph nodes, or lung if the life-threatening component of the uveal melanoma was in the liver and the extrahepatic disease was amenable to resection or radiation. The key study exclusion criteria were metastases in ≥50% of the liver parenchyma, Child-Pugh class B or C cirrhosis, or hepatitis B or C infection.
The patients received 3 mg/kg of melphalan hydrochloride/HDS based on ideal body weight (maximum dose, 220 mg) that was administered every 6 to 8 weeks for up to 6 infusions. The median number of infusions administered per patient was 4 (range, 1-6). In all, 37% of the 91 patients in the study received the maximum of 6 infusions.
The main efficacy outcomes were objective response rate (ORR) and duration of response (DOR), as assessed by an independent central review committee using RECIST V1.1. The results showed an ORR of 36.3% (95% confidence interval [CI], 26.4-47) and a median DOR of 14 months (95% CI, 8.3-17.7).
“This is a breakthrough therapy that will help a patient population that has very few treatment options,” said Jonathan S. Zager, MD, Chief Academic Officer and Surgical Oncologist at Moffitt Cancer Center, Tampa, FL, and lead principal investigator for the FOCUS trial. “The phase 3 trial was very positive in terms of overall response rate and durability of the responses, with very manageable toxicity.”
The most common (≥20%) adverse reactions and laboratory abnormalities in the study were thrombocytopenia, fatigue, anemia, nausea, musculoskeletal pain, leukopenia, abdominal pain, neutropenia, vomiting, increased alanine aminotransferase, prolonged activated partial thromboplastin time, increased aspartate aminotransferase, increased blood alkaline phosphatase, and dyspnea.
Overall, treatment with melphalan hydrochloride/HDS was permanently discontinued because of adverse events in 18% of the study patients; neutropenia was the most common cause of permanent treatment discontinuation. In addition, 14% of the patients had dose reductions, including 6% of patients because of decreased platelet count, 4.2% because of neutropenia, and 2.1%, each, because of anemia or thrombocytopenia.
The prescribing information for melphalan hydrochloride/HDS includes a boxed warning about the risk for severe periprocedural complications, including hemorrhage, hepatocellular injury, and thromboembolic events, as well as for myelosuppression associated with severe infection, bleeding, or symptomatic anemia. Because of these risks, melphalan hydrochloride/HDS is only available through a restricted Risk Evaluation and Mitigation Strategy (REMS) program called Hepzato Kit REMS.
Melphalan hydrochloride/HDS is contraindicated in patients who have active intracranial metastases or brain lesions with a propensity to bleed; have liver failure, portal hypertension, or known varices at risk for bleeding; had surgery or medical treatment of the liver in the past 4 weeks; have uncorrectable coagulopathy, including active cardiac conditions, worsening or new-onset congestive heart failure, significant arrhythmias, or severe valvular disease; have an inability to safely undergo general anesthesia; have allergies or hypersensitivity to melphalan; have allergies to a component or material used in melphalan hydrochloride/HDS, including an allergy to natural rubber latex; have an allergy or hypersensitivity to heparin or have heparin-induced thrombocytopenia; and in patients who have a severe allergic reaction to iodinated contrast that is not controlled by premedication with antihistamines and steroids.
The recommended dose of melphalan hydrochloride/HDS is 3 mg/kg, based on ideal body weight, with a maximum dose of 220 mg during a single infusion, that is administered every 6 to 8 weeks, for a maximum of 6 infusions.